The Use of a Complex Flavonoid as a Treatment for ALS
Elijah W. Stommel*, Brent T. Harris∞, David J. Graber ∞, Jeffrey A. Cohen*, Department of Medicine (Section of Neurology) *
Department of Pathology∞ Dartmouth-Hitchcock Medical Center (DHMC), Lebanon, NH 03756
Tel: 603-650-8615 Fax: 603-650-0458 Email: elijah.w.stommel@hitchcock.org
Abstract
We propose using sublingual LutiMax®, a molecular complex
of the bioflavonoids (luteolin and rutin) that target many of
the pathogenic mechanisms thought to be important in ALS.
LutiMax® was introduced into commerce as a dietary
supplement worldwide in 2002 by SYNORx, Inc. There is
substantial evidence to show that bioflavonoids are
neuroprotective by reducing neuroinflammation, reducing
pro-inflamatory cytokines and chemokines and reducing
neuronal apoptosis, all of which suggests an important role
for flavonoids in counteracting neurodegeneration. LutiMax®
has no known major side effects. We have followed a
relatively small number of ALS patients who appear to have
stabilized once they started taking LutiMax®. This
unexpected observation needs to be verified with a formal
clinical trial. Patients will be evaluated using the ALS
Functional Rating Scale (ALSFRS) as a primary outcome
with secondary outcomes being, survival, safety and FVC
measured every 3 months. With this phase II trial, 60 ALS
patients will be entered in a double-blind, placebo-controlled,
cross-over study. We plan to use LutiMax® for 12 months vs.
placebo in a cross-over with a latin square technique where
the patient will be switched from real medication to placebo
or visa-versa at six months. A wash out period of a week
between treatments will occur. Assuming 80% complete both
periods (i.e., receive both placebo and treatment) the study
will have sufficient power (80%) at a type I error rate of 5%
to detect an effect of treatment such that 75% of patients
have a better ALSFRS score following treatment, than
following placebo. The patients will have to meet strict
inclusion and exclusion criteria for the study including being
able to ingest the pills sublingually and having been
diagnosed with the disease for less than 1 year. There will be
no need to follow any specific blood labs as LutiMax® TM has
not been found to have any major toxicities. Because the
safety profile of LutiMax® is excellent, the expenses of the
trial should be relatively low. We envision involving 5 NEALS
associated centers in this trial.
L enhances proteosomal degradation of misfolded proteins33,
and both L and Q increase the redox sensitive transcription
factor (Nrf-2) mRNA and stabilize Nrf-2 to proteosomal
degradation56. L also activates the cell regulating protein,
Sirtuin57. L and Q block the transcription factor AP-127,51, and
immune activation in experimental autoimmune encephalitis
(EAE)41,58. L and Q block extracellular signal-regulated kinases
ERK1/2 and the protein kinase Akt59, modulate intracellular
calcium60-61 and increase mitochondrial efficiency and inhibit
glycogen synthase kinase 3 (GSK-3)30,62. Recent research on L
and Q show these bioflavonoids target autophagy63 MPTP
related Parkinson’s disease*56, astrocytic mediated apoptosis,
management of blood brain barrier (BBB) to T Cells and
macrophages*41,58, and IL-6 production in microglia by inhibiting
the mitogen-activated protein kinase JNK phosphorylation and
the activator protein (AP-1)*61. (*studies sponsored by SYNORx)
Three recent publications confirm the poor bioavailability of oral
L, two of which describe the dramatic increased oral
bioavailability of L when combined with R. Orally ingested
LutiMax® shows 1.9 to over 10 times greater plasma levels of L
than the same oral dose of L6. R is hydrolyzed to Quercetin (Q)
4-6 hours after ingestion7 and plays the role of Trojan Horse for L
as well as having complimentary pharmacokinetic effects on L6,8.
L and Q are some of the best inhibitors of superoxide
generation by xanthine oxidase9 (XO) and nicotinamide adenine
dinucleotide phosphate (NAPDH) oxidase in nature10-11, and they
block nitric oxide (NO) synthesis12-13 as well as quench the
hydroxyl radical14-15.
L and Q are both active in the mitochondria, effect apoptosis in
cancer cells by blocking glycolysis16-17, and they both are
neuroprotective to excitotoxins18-19, chemical oxidants20,
neurotoxins21, cytokines5, and inflammatory molecules22. R also
increase the synthesis of glutathione (GSH), glutathione
peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT)
23-26 and Q also promotes redox homeostasis24.
The recent research on L and the synergistic mixtures with R
provide a body of evidence to support the clinical evaluation of
LutiMax® in ALS. ALS is a multifactorial disease with multiple
pharmacologic targets, and the multifactorial pharmacodynamics
of L, R, and Q match many of the same targets at the
transcriptional to the enzymatic and metabolic level. Overall,
there are compelling arguments to try LutiMax® in a clinical trial
with ALS patients.
L, R, and Q block the reactive oxygen species (ROS)15,24,
cytokine27-28, and LPS induced expression of inflammatory
genes27, protein signaling molecules2,29, kinases3,30, and
inflammatory mediating enzymes including phopholipase A231,
phospholipase C32, protein kinase C (PKC)33, cyclooxygenase-2
enzyme (COX-2)34, inducible nitric oxide synthase (iNOS)
enzyme expression35-36, lipoxygenase37-38, TNF-alpha39-41,and
TNF-alpha induced nuclear factor-kappa B (NF-KB) activation
via I kappa B kinase beta (IKKB)42-43. The interleukins IL-1B5,28,
IL-244-45, IL-446, IL-547, IL-65,48, IL-849-50, IL-1044, IL-1242, and IL1351-52 as well as IFN-gamma28,53 all show inhibition or
modulation by L or Q or both. Both L and Q are also strong
inhibitors of IgE mediated allergic reactions54-55.
Proposed Trial
We feel that there is potential for LutiMax® as a treatment for 100 mm
ALS after observing some patients who appear to have stabilized
on this compound. We propose treating, through a multi-center
trial, 60 ALS patients with LutiMax®. With this phase II trial,
patients will be entered in a double-blind, placebo-controlled,
cross-over study. We plan to use LutiMax® for 12 months vs.
placebo in a cross-over with a latin square technique where the
patient will be switched form real medication to placebo or visaversa at six months. Assuming 80% complete both periods (i.e.,
receive both placebo and treatment) the study will have sufficient
power (80%) at a type I error rate of 5% to detect an effect of
treatment such that 75% of patients have a better ALSFRS score
following treatment, then following placebo. The patients will
have to meet strict inclusion and exclusion criteria for the study
including being able to ingest the pills sublingually. Patients
would be evaluated using the ALSFRS as a primary outcome
with secondary outcomes being survival and FVC, measured
every 3 months. A neurological screening exam will be done on
initial visit and then every three months. There will be no need to
follow any specific blood labs as LutiMax® has not been found to
be toxic in rats nor in humans64-66. No acute oral toxicity was
found with testing in mice using LutiMax® at 5.0 grams/kg of
body weight and 7.5 grams/kg of body weight as performed by
the Chinese Academy of Sciences, Institute of Materia Medica,
National Institute of Pharmacological Screening in Beijing in
2007 (SYNORx, Inc.,unpublished data). The lack of toxicity
should make compliance better and will reduce the budget for
the trial.
Bioflavonoids
Introduction
LutiMax®
is a molecular complex of the bioflavonoids
Luteolin(L) and Rutin(R). LutiMax® was introduced into
commerce as a dietary supplement worldwide in 2002 by
SYNORx, Inc. LutiMax® has not been shown to have any
serious side effects. LutiMax® has many targets for
neurodegenerative disease. The response appears to be
dose dependent, and there have been no demonstrable
biological effects to either pure L or R1. We, at DHMC,
have personally seen several ALS patients who appear to
have clinically stabilized while taking LutiMax®.
There is substantial evidence to show that flavonoids are
neuroprotective by reducing neuroinflammation, reducing
pro-inflamatory cytokines and chemokines and reducing
neuronal apoptosis all of which suggests an important role
for flavinoids in counteracting neurodegeneration2-5. As no
rigorous clinical trial has been undertaken, we propose to
look at this potentially promising compound in the setting
of ALS.
Luteolin
Quercetin
Rutin
100 mm
A dose of LutiMax® (each lozenge contains 100mg of luteolin
and 100mg of rutin) will ultimately be 8 lozenges sublingually 4
times a day. We expect patients to be able to get to this dose
within a week of starting. The sublingual delivery for LutiMax® is
a convenient reliable method which avoids first-pass
metabolism in the liver and pre-systemic elimination in the
gastrointestinal tract67. A washout period of a week will be
initiated between treatments. LutiMax® has made a placebo
lozenge which is indistinguishable by taste, texture and color to
the standard lozenge. The placebo lozenge has been tested by
chromatography.
High intakes of carbohydrate and low intakes of fat and some
kinds of fatty acids may, when combined appear to increase the
risk of ALS68. A ketogenic diet has been proposed as a therapy
for ALS69-70. LutiMax® works best in a low-carbohydrate diet,
especially low in sugars (Thomas Lahey: personal
observations). We will recommend a high protein, high
unsaturated fat, low carbohydrate diet with a target of 3000
calories per day to maintain weight and muscle mass. To
accomplish this, a nutritionist will provide an integrated
shopping list and meal recommendations and patients will keep
a dietary record.
Funding for this project is still being pursued. The budget for this
trial should be relatively small.
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LutiMax vs. Controls (MGH study)